The invention relates to methods of treating neuropathic pain, tinnitus, and other disorders, and to pharmaceutical compositions useful in the treatment of neuropathic pain and tinnitus.
Chemically, ketoprofen is 2-(3-benzoylphenyl)-propionic acid, and has the following structure: 
Racemic ketoprofen (a mixture of the R(xe2x88x92) and S(+) enantiomers) is sold under the tradenames Orudis(copyright) and Oruvail(copyright) for the treatment of inflammation. Physicians Desk Reference 52nd Ed., p. 3092 (1998). Generally, ketoprofen is considered to be a nonsteroidal anti-inflammatory agent (xe2x80x9cNSAIDxe2x80x9d). NSAIDs are believed to exhibit activity as COX-1 or COX-2 enzyme inhibitors. Most NSAIDs are believed to cause gastrointestinal irritation.
The S(+) enantiomer of ketoprofen has long been thought to possess most, if not all, of the pharmacological activity of the racemate. See, e.g., Yamaguchi et al., Nippon Yakurigaku Zasshi. 90:295-302 (1987); Abas et al., J. Pharinacol. Exp. Ther., 240:637-641 (1987); and Caldwell et al., Biochem. Pharrnacol. 37:105-114 (1988). Indeed, U.S. Pat. Nos. 4,868,214, 4,962,124, and 4,927,854 each allege that the analgesic activity of ketoprofen resides exclusively in the S(+) enantiomer.
However, U.S. Pat. No. 5,331,000 discloses the use of the optically pure R(xe2x88x92) enantiomer as an antipyretic and analgesic agent to treat, with reduced gastrointestinal irritancy.
The effective treatment of pain requires an understanding of its physiology. It is well known, however, that stimuli which activate pain receptors in one tissue may not activate pain receptors in another. For example, pricking or cutting which causes pain in skin tissue does not cause pain in the stomach or intestine. The causes of pain in skeletal muscle, joints, and arteries can also differ. Principles of Neurology, 6th ed., Adams, R. D., et al., eds. (McGraw-Hill: 1997), pp. 133-134. Consequently, methods useful for relieving one type of pain are often less effective, or even ineffective, when applied to the alleviation of others.
In general, neuropathic pain is persistent and is characterized by burning, gnawing, aching, shooting, or lancinating sensations. It is frequently associated with hyperesthesia, hyperalgesia, allodynia, and hyperpathia, and in some cases by sensory deficit or autonomic dysfunction. Unfortunately, and unlike other types of pain, neuropathic-pain tends to respond poorly to analgesic medication. Principles of Neurology, 6th ed., Adams, R. D., et al., eds. (McGraw-Hill: 1997), p. 140.
Depending on the particular nerves involved, a particular instance of neuropathic pain can be classified as a central or peripheral neuropathy. Central neuropathies arise from spinal cord, brainstem, thalamic, and cerebral damage or disease, while peripheral neuropathies arise from damage or disease of peripheral nerves. Specific peripheral neuropathies include, but are not limited to: thoracic outlet obstruction syndromes; compression and entrapment neuropathies such as ulnar nerve palsey, carpal tunnel syndrome, peroneal nerve palsey, radial nerve palsey; and Guillain-Barrxc3xa9 syndrome. The Merck Manual, 16th ed., 1518-1522 (1992).
Neuropathic, or neurogenic, pain arises from the direct stimulation of nervous tissue. Neuropathic pain encompasses a wide variety of disorders involving single and multiple nerves. These include, but are not limited to, trigeminal neuralgia and disorders due to herpes zoster, diabetes, and trauma (including causalgia); spinal arachnoiditis and spinal cord injuries; and the thalamic pain syndrome of Dxc3xa9jerine-Roussy. Principles of Neurology, 6th ed., Adams, R. D., et al., eds. (McGraw-Hill: 1997), p. 140.
Neuropathic pain is caused by a variety of factors including, but not limited to: trauma caused by injury or surgical operation; tumors; bony hyperostosis; casts; crutches; prolonged cramped postures; hemorrhage into a nerve; exposure to cold or radiation; collagen-vascular disorders; metabolic diseases such as diabetes; infectious diseases such as Lyme disease and HIV; toxins such as emetine, hexobarbital, barbital, chlorobutanol, sulfonamides, phenytoin, nitrofurantoin, the vinca alkaloids, heavy metals, carbon monoxide, triorthocresylphosphate, orthodinitrophenol, and other solvents and industrial poisons; autoimmune reactions; nutritional deficiency, and vitamin B deficiency in particular; and metabolic disorders such as hypothyroidism, porphyria, sarcoidosis, amyloidosis, uremia and diabetes. The Merck Manual, 16th ed., 1518 (1992).
Because so many causes of neuropathic pain exist, and because it tends to respond poorly to analgesic medication, the discovery of drugs that safely and effectively aid in its relief has been difficult.
Like neuropathic pain, tinnitus is often thought of as a subjective disorder; numerous causes have thus been postulated for it. A patient with tinnitus typically perceives a sound in the head or the ears without an evident external stimulus. Such sounds often have a buzzing, ringing, roaring, whistling, or hissing quality, or may be more complex and vary over time. Vesterager, V., BMJ, 314:728-31(1997).
Tinnitus can result from nearly all ear disorders, including, but not limited to: obstruction of the external auditory canal; infectious processes such as external otitis, myrignitis, otitis media, labyrinthitis, petrositis, syphilis and meningitis; eustachian tube obstruction; otosclerosis; middle ear neoplasms such as the glomus tympanicum and glomus jugulare tumors; Meniere""s disease; arachnoiditis; cerebellopontine angle tumors; cardiovascular diseases such as hypertension, arteriosclerosis and aneurysms; anemia; hypothyroidism; hereditary sensorineural or noise-induced hearing loss; and acoustic trauma. The Merck Manual, 16th ed., 2324 (1992). Tinnitus can also result from ototoxicity caused by acute intoxication or long-term administration or exposure to salicylates, quinine and its synthetic analogues, aminoglycoside antibiotics, diuretics, carbon monoxide, heavy metals, and other drugs or toxins. Seligmann, H., et al., Drug Safety 14(3):198-212 (1996). Psychological causes have also been suggested. Vesterager, V., BMJ, 314:728-31 (1997).
The biological mechanism which causes or relates to tinnitus remains unclear. Some researchers have suggested that it may result from a decrease of the normal GABAergic inhibitory influence of neurons in the inferior colliculus. Mxc3x8ller, A. R., Am. J. Otology, 18:577-585 (1997). Others have argued that the disorder results from pathological changes of neurons within the inner ear. See, e.g., Ehrenberger, K., and Felix, D., Acta Otolaryngol (Stockh), 115:236-240 (1995). It has also been suggested that tinnitus generation might be similar to the xe2x80x9cgate theoryxe2x80x9d of pain. See, e.g., Murai, Kazuo, et al., Am. J. Otology 13(5):454-464 (1992); Sahley, T. L., et al., Ear and Hearing 17:341-353 (1996); and Sahley, T. L., et al., Ear and Hearing 17:552-558 (1996).
Because its mechanism is poorly understood, the discovery of drugs that are effective in the treatment of tinnitus has been slow. Some researchers have alleged that administration of the local anesthetic lidocaine can reduce symptoms of the disorder, but its alleged effectiveness is of short duration. Lyttkens, L., Scand. Audiol. Suppl. (Sweden) 26:27-31 (1986); and Murai, Kazuo, et al., Am. J. Otology 13(5):454-464 (1992). Other drugs alleged to be somewhat effective in the treatment of tinnitus include oxazepam, clonazepam, glutamic acid, streptomycin, and eperisone hydrochloride. Murai, Kazuo, et al., Am. J. Otology 13(5):454-464 (1992). Unfortunately, these and other drugs are allegedly effective in only a few patients. More important, those drugs that are reportedly the most effective (e.g., lidocaine, oxazepam and clonazepam) can cause a wide variety of adverse effects. These include, but are not limited to, numbness, tingling, light-headedness, blurred speech, nausea, dermatitis, uricarial exanthema, vomiting, tremor, visual disturbance, disequilibrium, rashes, headache, diplopia, sedation, and sleepiness. Murai, Kazuo, et al., Am. J. Otology 13(5):454-464 (1992). There thus exists a need for a safe and effective method of treating tinnitus.
The invention is directed to methods of treating or preventing neuropathic pain, tinnitus, and other disorders, as well as pharmaceutical compositions suitable for the treatment of neuropathic pain and tinnitus.
This invention encompasses the use of optically pure R(xe2x88x92)-ketoprofen for treating or preventing neuropathic pain, which is generally not treated by anti-inflammatory, analgesic, or antipyretic agents. Moreover, the invention encompasses the use of optically pure R(xe2x88x92)-ketoprofen to treat or prevent tinnitus or ringing in the ears, which has heretofore been notoriously difficult to treat with any therapeutic agent.
As used herein, the term xe2x80x9cmammalxe2x80x9d includes human. The terms xe2x80x9chumanxe2x80x9d and xe2x80x9cpatientxe2x80x9d are used interchangeably herein.
As used herein, the term xe2x80x9ctreating neuropathic painxe2x80x9d means alleviating, ameliorating, reducing, or relieving at least one symptom of acute or chronic neuropathic pain. Symptoms of acute or chronic neuropathic pain include, but are not limited to, burning, gnawing, aching, shooting, or lancinating sensations, sensory deficit, and autonomic dysfunction.
As used herein, the term xe2x80x9ctreating tinnitusxe2x80x9d means alleviating, ameliorating, reducing, or relieving at least one symptom of acute or chronic tinnitus. Symptoms of acute or chronic tinnitus include, but are not limited to, the hearing of buzzing, ringing, roaring, whistling, or hissing sounds.
As used herein, the term xe2x80x9cpatient at risk of tinnitusxe2x80x9d means a patient who is suffering from a disease or condition that is associated with tinnitus. Diseases or conditions associated with tinnitus include, but are not limited to: obstruction of the external auditory canal; infectious processes including external otitis, myrignitis, otitis media, labyrinthitis, petrositis, syphilis and meningitis; eustachian tube obstruction; otosclerosis; middle ear neoplasms such as the glomus tympanicum and glomus jugulare tumors; Meniere""s disease; arachnoiditis; cerebellopontine angle tumors; cardiovascular diseases including hypertension, arteriosclerosis and aneurysms; anemia; hypothyroidism; hereditary sensorineural or noise-induced hearing loss; acoustic trauma; ototoxicity caused by acute intoxication or long-term administration or exposure to drugs or toxins-including salicylates, quinine and its synthetic analogues, aminoglycoside antibiotics, diuretics, carbon monoxide, and heavy metals; and psychological disorders.
As used herein, the term xe2x80x9csubstantially free of its S(+) enantiomerxe2x80x9d means that the composition contains less than about 10% by weight S(+)-ketoprofen. Preferably, the term xe2x80x9csubstantially free of its S(+) enantiomerxe2x80x9d means that the composition contains less than about 5% by weight S(+)-ketoprofen. Most preferably, the term xe2x80x9csubstantially free of its S(+) enantiomerxe2x80x9d means that the composition contains less than about 1% by weight of S(+)-ketoprofen. These percentages are based upon the total amount of ketoprofen present in the composition. The terms xe2x80x9csubstantially optically pure R(xe2x88x92) enantiomer of ketoprofenxe2x80x9d or xe2x80x9csubstantially optically pure R(xe2x88x92)-ketoprofenxe2x80x9d and xe2x80x9coptically pure R(xe2x88x92)-ketoprofenxe2x80x9d or xe2x80x9coptically pure R(xe2x88x92) enantiomer of ketoprofenxe2x80x9d are also encompassed by the above-described amounts.
As used herein, the term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic organic or inorganic bases. Suitable organic bases include, but are not limited to, lysine, N,Nxe2x80x2-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable inorganic bases include, but are not limited to, alkaline and earth-alkaline metals such as aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
The invention involves using optically pure R(xe2x88x92)-ketoprofen to effectively treat neuropathic pain, tinnitus, and related disorders. The invention encompasses treating these disorders without causing adverse effects associated with racemic ketoprofen. Adverse effects associated with racemic ketoprofen include, but are not limited to: gastrointestinal irritation such as dyspepsia, nausea, abdominal pain, diarrhea, constipation, flatulence, vomiting, and stomatitis; anorexia; headache; dizziness; CNS inhibition such as somnolence, malaise, and depression; CNS excitation such as insomnia and nervousness; hypertension; palpitation; tachycardia; congestive heart failure; peripheral vascular disease, and tinnitus.
A first embodiment of the invention encompasses a method of treating neuropathic pain in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of substantially optically pure R(xe2x88x92)-ketoprofen, or a pharmaceutically acceptable salt, solvate, or clathrate thereof. Preferably, the therapeutically effective amount of substantially optically pure R(xe2x88x92)-ketoprofen, or pharmaceutically acceptable salt, solvate, or clathrate thereof, is between about 1 mg and about 2000 mg, more preferably between about 5 mg and about 1500 mg, and most preferably between about 10 mg and about 1000 mg. Preferably, the substantially optically pure R(xe2x88x92)-ketoprofen comprises less than about 10% by weight S(+)-ketoprofen, more preferably less that about 5% by weight S(+)-ketoprofen, and most preferably less than about 1% by weight S(+)-ketoprofen.
This embodiment of the invention encompasses a method of treating a central neuropathy in a mammal. Preferably, the central neuropathy arises from the damage or disease of the spinal cord, brainstem, thalamus, or cerebellum.
The first embodiment of the invention also encompasses a method of treating a peripheral neuropathy in a mammal. Preferred peripheral neuropathies include, but are not limited to: thoracic outlet obstruction syndromes; compression and entrapment neuropathies such as ulnar nerve palsey, carpal tunnel syndrome, peroneal nerve palsey, and radial nerve palsey; and Guillain-Barrxc3xa9 syndrome.
This first embodiment of the invention further encompasses compositions adapted for the treatment of a mammal suffering from neuropathic pain which comprise a therapeutically effective amount of substantially optically pure R(xe2x88x92)-ketoprofen, or a pharmaceutically acceptable salt, solvate, or clathrate thereof, said amount being sufficient to alleviate at least one symptom of neuropathic pain. The embodiment encompasses single unit dosage forms of substantially optically pure R(xe2x88x92)-ketoprofen which comprise from about 1 mg to about 2000 mg, more preferably from about 5 mg to about 1500 mg, and most preferably from about 10 mg to about 1000 mg of optically pure R(xe2x88x92)-ketoprofen, or a pharmaceutically acceptable salt, solvate, or clathrate thereof. Preferably, the substantially optically pure R(xe2x88x92)-ketoprofen comprises less than about 10% by weight S(+)-ketoprofen, more preferably less that about 5% by weight S(+)-ketoprofen, and most preferably less than about 1% by weight S(+)-ketoprofen.
Another embodiment of the invention encompasses a method of treating or preventing tinnitus or ringing in the ear in a patient which comprises administering to a patient in need of such treatment a therapeutically effective amount of substantially optically pure R(xe2x88x92)-ketoprofen, or a pharmaceutically acceptable salt, solvate, or clathrate thereof. Preferably, the therapeutically effective amount of substantially optically pure R(xe2x88x92)-ketoprofen, or pharmaceutically acceptable salt, solvate, or clathrate thereof, is between about 1 mg and about 2000 mg, more preferably between about 5 mg and about 1500 mg, and most preferably between about 10 mg and about 1000 mg. Preferably, the substantially optically pure R(xe2x88x92)-ketoprofen comprises less than about 10% by weight S(+)-ketoprofen, more preferably less that about 5% by weight S(+)-ketoprofen, and most preferably less than about 1% by weight S(+)-ketoprofen.
This embodiment of the invention also encompasses a method of preventing tinnitus or ringing in the ear in a patient at risk of tinnitus.
This embodiment of the invention further encompasses a method of treating tinnitus or ringing in the ear associated with a disease or condition selected from the group consisting of: obstruction of the external auditory canal; infectious processes including external otitis, myrignitis, otitis media, labyrinthitis, petrositis, syphilis and meningitis; eustachian tube obstruction; otosclerosis; middle ear neoplasms such as the glomus tympanicum and glomus jugulare tumors; Meniere""s disease; arachnoiditis; cerebellopontine angle tumors; cardiovascular diseases including hypertension, arteriosclerosis and aneurysms; anemia; hypothyroidism; hereditary sensorineural or noise-induced hearing loss; acoustic trauma; ototoxicity caused by acute intoxication or long-term administration or exposure to drugs or toxins including salicylates, quinine and its synthetic analogues, aminoglycoside antibiotics, diuretics, carbon monoxide, and heavy metals; and psychological disorders.
This embodiment of the invention also includes compositions adapted for the treatment of a patient suffering from tinnitus which comprise a therapeutically effective amount of optically pure R(xe2x88x92)-ketoprofen or a pharmaceutically acceptable salt, solvate, or clathrate thereof, said amount being sufficient to alleviate at least one symptom of tinnitus. The embodiment encompasses single unit dosage forms of substantially optically pure R(xe2x88x92)-ketoprofen which comprise from about 1 mg to about 2000 mg, more preferably from about 5 mg to about 1500 mg, and most preferably from about 10 mg to about 1000 mg of optically pure R(xe2x88x92)-ketoprofen, or a pharmaceutically acceptable salt, solvate, or clathrate thereof. Preferably, the substantially optically pure R(xe2x88x92)-ketoprofen comprises less than about 10% by weight S(+)-ketoprofen, more preferably less that about 5% by weight S(+)-ketoprofen, and most preferably less than about 1% by weight S(+)-ketoprofen.
A final embodiment of the invention encompasses compositions comprising R(xe2x88x92)-ketoprofen and a pharmaceutically acceptable carrier.
Racemic ketoprofen can be made by the method described in U.S. Pat. No. 3,641,127, which is hereby incorporated by reference. The R(xe2x88x92) enantiomer of ketoprofen can be readily obtained from the racemate using, for example, high performance liquid chromatography (HPLC) or an optically active resolving base. A preferred method of resolving the R(xe2x88x92) enantiomer is disclosed in U.S. Pat. No. 5,677,469, which is incorporated herein by reference. Other methods suitable for resolving R(xe2x88x92)-ketoprofen are disclosed by, for example, U.S. Pat. Nos. 4,983,765 and 4,973,745, both of which are incorporated herein by reference. See, also, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
Enzymatic biocatalytic resolution may also be used to isolate the optically pure R(xe2x88x92) enantiomer from racemic ketoprofen. See, e.g., U.S. Pat. Nos. 5,057,427, and 5,077,217, both of which are incorporated herein by reference. A preferred enzymatic method is disclosed by U.S. Pat. No. 5,457,051, which is also incorporated herein by reference.
Optically pure R(xe2x88x92)-ketoprofen can further be prepared from the corresponding acrylic acid by catalytic hydrogenation using a chiral catalyst. See, e.g., U.S. Pat. Nos.: 5,198,561; 5,202,473; 5,202,474; 5,233,084; and 5,097,064, all of which are incorporated herein by reference.
Pharmaceutically acceptable salts of R(xe2x88x92)-ketoprofen are readily made using techniques well known to those skilled in the art. Examples of such techniques, and the salts made therefrom, are disclosed by U.S. Pat. No. 5,808,069, which is incorporated herein by reference.
The magnitude of a prophylactic or therapeutic dose of R(xe2x88x92)-ketoprofen (referred to herein as the xe2x80x9cactive ingredientxe2x80x9d) in the acute or chronic management of disease (i.e., neuropathic pain, tinnitus, or a related disorder) will vary with the severity of the condition to be treated and the route by which the drug is administered. The dose, and perhaps the dose frequency, will also vary according to the age, body weight, and response of the individual patient. In general, the total daily dose range of R(xe2x88x92)-ketoprofen is from about 1 mg to about 2000 mg, in single or divided doses. Preferably, a daily dose range should be between about 5 mg and about 1500 mg, in single or divided doses. More preferably, a daily dose range should be between about 10 mg and about 1000 mg, in single or divided doses. In managing the patient, the therapy should be initiated at a lower dose, perhaps about 1 mg to about 200 mg, and increased up to about 1000 mg or higher depending on the patient""s global response. It is further recommended that infants, children, patients over 65 years, and those with impaired renal or hepatic function, initially receive low doses, and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust or terminate therapy in conjunction with individual patient response. The terms xe2x80x9ctherapeutic amountxe2x80x9d and xe2x80x9ctherapeutically effective amountxe2x80x9d are encompassed by the above-described dosage amounts and dose frequency schedules.
In practical use, optically pure R(xe2x88x92)-ketoprofen can be combined as the active ingredient in intimate admixture with a pharmaceutically acceptable carrier according to conventional pharmaceutical compounding techniques. The pharmaceutically acceptable carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral, parenteral (including intravenous, subcutaneous, intrathecal, and intramuscular), transdermal, and topical. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media or excipients may be employed. These include, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as suspensions, elixirs and solutions; or aerosols; or excipients such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, capsules, caplets, and tablets. Solid oral preparations are generally preferred over liquid ones. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical pharmaceutically acceptable excipients are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Preferred solid oral preparations are tablets and capsules.
Pharmaceutical stabilizers may be used to stabilize compositions comprising optically pure R(xe2x88x92)-ketoprofen, or pharmaceutically acceptable salts, solvates, or clathrates thereof. Acceptable stabilizers include, but are not limited to, L-cysteine hydrochloride, glycine hydrochloride, malic acid, sodium metabsulfite, citric acid, tartaric acid, and L-cystine dihydrochloride. See, e.g., U.S. Pat. Nos.: 5,731,000; 5,763,493; 5,541,231; and 5,358,970, all of which are incorporated herein by reference.
In addition to the common dosage forms set out above, the active ingredient (i.e., optically pure R(xe2x88x92)-ketoprofen) can be administered by controlled release means and/or delivery devices capable of releasing the active ingredient at a rate required to maintain constant pharmacological activity for a desirable period of time. Such dosage forms provide a supply of a drug to the body during a predetermined period of time and thus maintain drug levels in the therapeutic range for longer periods of time than conventional non-controlled formulations. Examples of controlled release pharmaceutical compositions and delivery devices which may be adapted for the administration of the active ingredient of the invention are described in U.S. Pat. Nos.: 3,847,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,610; 4,769,027; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,566; and 5,733,566, the disclosures of which are incorporated herein by reference.
Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets, caplets, or tablets or aerosol sprays, each containing a predetermined amount of the active ingredient as a powder, as granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy which include the step of bringing into association the active ingredient with a pharmaceutically acceptable carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with a liquid pharmaceutically acceptable carrier or a finely divided solid pharmaceutically acceptable carrier, or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, disintegrating agent, and/or surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Preferably, each tablet contains from about 0.5 mg to about 1000 mg of the active ingredient, and each cachet or capsule contains from about 0.5 mg to about 2000 mg of the active ingredient, more preferably from about 5 mg to about 1500 mg, and most preferably between about 10 mg and about 1000 mg.
The invention is further defined by reference to the following examples describing in detail the preparation of the compound and compositions of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.